Despite remarkable advances in our understanding of the biology of malaria over the last 30 years, malaria elimination remains elusive in Malawi, among other sub-Saharan African countries. The applicant has focused her academic career on using genetics and epidemiology to address key public health questions related to treating and preventing malaria, and to training U.S.- and Malawi-based investigators to conduct patient- oriented malaria research to this end. This K24 award builds on her overarching goal of using translational research to improve malaria treatment and prevention now and will prepare her and her trainees to develop strategies for malaria elimination in Malawi and throughout sub-Saharan Africa. The specific research aims of this proposal focus on interventions to prevent malaria in two vulnerable populations: pregnant women and their babies, in whom the malaria risk is well known but for whom preventive strategies are inadequate, and school-age children, a population newly recognized to suffer from high rates of malaria infection. Pregnant women routinely receive intermittent treatment two to three times during pregnancy to prevent malaria, but the efficacy of currently used medication is compromised due to widespread resistance and new strategies are urgently needed. The applicant and her team recently completed a trial comparing intermittent preventive treatment to continuous prophylaxis to prevent malaria during pregnancy in Malawi. In this proposal, clinical, molecular, genomic and immunological data will be analyzed to test the hypothesis that intermittent treatment and continuous prophylaxis to prevent malaria during pregnancy will have different effects on maternal and neonatal outcomes, maternal susceptibility to malaria in subsequent pregnancies and infant immunity to malaria. To further investigate the burden of malaria infection and transmission potential in school-age children, the applicant has added school-based surveys to on-going cross-sectional studies. They will test the hypothesis that children at high risk of carrying malaria infection, including gametocytes, can be reached through school-based interventions. The applicant will take advantage of the career development components of this award to enrich her knowledge base and international partnerships that will allow her to expand the scope of her research and develop new interventions in Malawi. This proposal includes an integrated, comprehensive mentoring plan to train U.S.- and Malawi-based investigators in the technical, scientific and professional skills required to succeed in patient-oriented research. The applicant and her research team strive to design hypothesis-driven studies that lead to evidence-based interventions to improve the health of those who suffer from malaria and contribute scientific insight to help eradicate malaria.